There are few if any consistently effective treatments for the visceral pain associated with inflammatory bowel diseases such as ulcerative colitis, or functional bowel disorders such as Irritable Bowel Syndrome. Given the prevalence of these disorders and the fact that pain is a primary complaint of those who suffer, identification of nove approaches for the treatment of visceral pain is highly significant. The focus central nervous system has been the focus of altered GABA signaling in the context of pain. Even for the primary afferents essential for transmitting the pain signal from the periphery, the focus has been on GABA regulation of central terminals. Indeed, we and others have described a number of changes in the central terminals of nociceptive afferents resulting in a shift in GABAA-receptor (GAR) signaling from inhibition to excitation, enabling GABA to contribute to the pain and hypersensitivity of inflammation. But what if GAR signaling at the peripheral terminals of nociceptive afferents also contributes to the regulation of nociceptive signaling? After all, GARs are also transported to the peripheral terminals of nociceptive afferents. In the colon, GABAergic enteric neurons, epithelial cells and endocrine cells are potential sources of GABA. Preliminary data indicate that in the absence of tissue injury, endogenous GABA released within the colon serves to attenuate the excitability of colonic afferents. Strikingly, there is a loss of periphera GAR inhibition of colonic afferents in a model of inflammatory colonic hypersensitivity (i.e. IBD-like) and the emergence of GAR-dependent excitation of colonic afferents non-inflammatory (i.e. IBS-like) persistent colonic hypersensitivity. These changes in GAR signaling are associated with a decrease in GABA synthetic enzymes in the IBD-like model and increases in GABA regulatory machinery in the IBS-like model. Thus, we hypothesize that a distinct pattern of changes in peripheral GAR signaling contributes to the colonic hypersensitivity observed in inflammatory and non- inflammatory visceral pain disorders. Experiments designed to test this hypothesis as well as identify mechanisms underlying the changes in GAR signaling are described under the following three Specific Aims. First, we propose to determine mechanisms underlying GAR-mediated suppression of afferent activity in the absence of tissue injury in the mouse colon. Second, we will determine the mechanisms underlying the changes GAR-mediated inhibition of colonic afferents in models of inflammatory and non-inflammatory colonic hypersensitivity. Third, we will establish a causal link between changes in GAR signaling mechanisms and colonic hypersensitivity. The proposed studies have the potential to transform the current view of GAR signaling to include the peripheral control of afferent excitability. More importantly, they may suggest novel approaches for the management of visceral pain.